Retinitis Pigmentosa (RP) and Leber Congenital Amaurosis (LCA) are among the many retinal degenerative diseases that affect millions of people. RP and LCA can be caused by malfunction of many genes, such as the human Crumbs1 (CRB1) gene. The detailed molecular etiology of CRB1-related RP and LCA is unclear. The objective of this proposal is to test an overall hypothesis that proper targeting and functioning of Crb2a and Crb2b complexes play essential roles in photoreceptor development. We propose to use zebra fish to model how Crb homologs and their associated proteins play roles in retinal development and how pathogenetic mutations in human CRB1 gene affect its functions. In zebra fish three Crb proteins (Crb1, Crb2a, and Crb2b) are expressed in the photoreceptor layer. We proposed three aims. First, test the hypothesis that Crb2a mediate a novel type of photoreceptor-photoreceptor (P-P) adhesion, which can be affected by a Crb2a mutation that is equivalent to an identified recessive pathogenetic mutation in human CRB1. Second, test the hypothesis that P-P adhesion mediated by Crb2b is essential for photoreceptor survival and patterning. We will also test that a mutation in Crb2b that is equivalent to an identified mutation in human CRB1 can cause retinal degeneration. Third, test the hypothesis that spatial and temporal regulation of the Ponli protein is essential for the morphogenesis of certain cones. The proposed research will provide insights into photoreceptor pattern formation and the maintenance of the photoreceptor layer. In addition, it will improve understanding of the molecular etiology of certain human RP and LCA diseases and provide clues to other retinal degeneration diseases. Our long-term goal is to find effective treatments for human retinal degeneration conditions by deciphering the molecular and cellular mechanisms of retinal cellular pattern formation. PUBLIC HEALTH RELEVANCE: Retinitis Pigmentosa (RP) and Leber Congenital Amaurosis (LCA) are among the many retinal degenerative diseases that affect millions of people. The proposed research will help us to better understand the molecular etiology of certain human RP and LCA diseases and to provide clues to other retinal degenerative diseases as well. Ultimately, the study will assist us in reaching the long-term goal of deciphering the molecular and cellular mechanisms of retinal cellular pattern formation and using such knowledge for finding effective treatments for human retinal degenerative conditions.